The incidence of Alzheimer's disease (AD) is steadily increasing with the aging of the U.S. population, and there are still no highly effective treatments. Amyloid-[unreadable] peptides (A[unreadable]) and the microtubule-associated protein tau compose the pathological hallmarks of AD. Considerable effort has been devoted to development of anti- A[unreadable] therapeutics, but disappointing results of early clinical trials has also broadened interest in other targets, notably tau. However, targeting a protein like tau that is abundant in the normal brain requires adequate knowledge of how it contributes to disease, and our understanding of tau's role in AD pathogenesis remains incomplete, hampering development of tau-based therapies for AD. We recently found that reducing tau expression has robust protective effects in multiple mouse models of AD, preventing cognitive deficits, premature mortality, impairment of synaptic plasticity, and epileptiform activity. These observations form the basis of the current application, capitalizing on this unique opportunity to understand how tau mediates or enables the effects of A[unreadable]. This application uses a new conditional mouse model of tau reduction to address several questions related to tau's role downstream of A[unreadable] in AD-related pathogenesis. In Aim 1, we address the potential therapeutic relevance of tau reduction by determining if tau reduction in adulthood is protective in mouse models of AD. In Aim 2, we address the cellular mechanisms underlying these effects by determining the effects of tau reduction in excitatory vs. inhibitory neurons. In Aim 3, we test a hypothesized molecular mechanism for these protective effects by determining how tau reduction prevents altered expression of ion channels controlling cellular excitability. PUBLIC HEALTH RELEVANCE: Alzheimer's disease afflicts over 5 million people in the United States, imposing huge personal costs on patients and their families and tremendous financial costs on our health care system. The incidence of AD is projected to grow steadily over the next several decades due to aging of the US population. The proposed research addresses a potential mechanism for preventing the effects of the toxic proteins believed to cause Alzheimer's disease.